Nicotine tablet

ABSTRACT

The invention relates to an orally disintegrating nicotine tablet for nicotine craving relief comprising a pressed powder formulation, the tablet being designed to disintegrate within a period of less than 60 seconds upon oral administration, the powder formulation comprising an amount of nicotine and a pH regulating agent.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application claims priority to Danish Patent Application No. PA2017 70925, filed Dec. 8, 2017, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to the field of fast disintegratingtablets. In particular, the present invention pertains to formulationsand methods used to employ nicotine more efficiently from fastdisintegrating tablets applied orally by the sublingual or buccal route.

BACKGROUND OF THE INVENTION

Nicotine-releasing tablets applied for the purpose of providing arelease of nicotine in a user's mouth over a certain period iswell-known. Much effort has in prior art been put into emulating thenicotine release and oral perception of a cigarette when it is smoked bya user, which means that release profiles from nicotine tablets havebeen thoroughly investigated in prior art.

It is however an established fact that the one-to-one smoking-emulationis yet to be achieved with other means than a cigarette.

SUMMARY

The invention relates to an orally disintegrating nicotine tablet fornicotine craving relief comprising a pressed powder formulation, thetablet being designed to disintegrate within a period of less than 60seconds upon oral administration, the powder formulation comprising anamount of nicotine and a pH regulating agent.

One advantage of the invention may be that effective nicotine cravingrelief is obtained while at the same time minimizing burning in thethroat. A significant challenge with oral administration of nicotine isthat it often leads to a very unpleasant burning sensation in thethroat. This burning sensation is normally worsened when increasing therelease rate of nicotine. Thus, obtaining effective nicotine cravingrelief and also at the same time minimizing burning in the throat ishighly surprising.

One advantage of the invention may be that by obtaining a very fastdisintegration of the tablet within a period of less than 60 secondsupon oral administration, and thereby facilitating fast release ofnicotine together with pH regulating agent, a high concentration ofnicotine combined with optimized pH is achieved in the oral cavity.

Furthermore, by ensuring the very fast disintegration of the tablet asdescribed above, the tablet facilitates user compliance withinstructions, such as not swallowing or spitting within a given timeperiod from oral administration. When delivering nicotine slowly to theoral cavity, the user will eventually have to spit or swallow due tosaliva generation, and may thus swallow or spit out unabsorbed nicotine,which is thus wasted. By keeping the period for disintegration veryshort and below 60 seconds upon oral administration, a very highconcentration of nicotine and optimized pH may be obtained for arelatively long period before the user swallows or spits out.

A further advantage of the invention may be that the above describedfacilitation of high nicotine concentration and optimized pH may beconcentrated locally in the oral cavity, such as sublingually, canfacilitate absorption of nicotine into the bloodstream even further.

Contrary to expectations, experiments have shown that the permeabilityof nicotine across the buccal mucosa decreases relatively little whenincreasing the concentration of nicotine. For example, experiments haveshown that an increase in the concentration of nicotine from 100microgram/mL to 14,000 microgram/mL results in a decrease of about afactor of two. This is highly surprising and is utilized by aiming forconcentrations of nicotine in the oral cavity, which are much higherthan previously seen or desired. The present delivery vehicle thusbenefits and aims for very high nicotine content in the oral cavity,thereby increasing the nicotine uptake. Furthermore, it has beenrealized that the effect of nicotine concentrations is thus at leastcomparable to the effect of pH regulation in the oral cavity. This iscontrary to any expectations.

The meaning of being designed to disintegrate upon oral administrationis that the tablet due to reaction with saliva already in the mouth andsaliva optionally generated as a response to the inserted tablet as suchwhen inserted into the mouth will disintegrate as a tablet. Such tabletmay e.g. be referred to within the art as an orally disintegratingtablet (ODT: orally disintegrating tablet). Here the meaning of beingdisintegrated is the process where the oral dosage form falls apart ordisintegrates in to smaller aggregates and as defined by EuropeanPharmacopeia 2.9.1 “Disintegration of tablets and capsules”. The timeperiod of obtaining the desired disintegration, here less than 60seconds, may be designed through use of materials such as polyols orbinders known within the art. The tablet disintegration time should alsoconsider the tablet manufacturing process, as a e.g. pressure force mayinfluence how disintegrable the tablet may end up being when finalized.For specific tablets, a number of parameters is to be considered,hereunder composition and content of individual ingredients, hereunderamount and form of nicotine, amount and form of disintegrant pressureforce used, type of orally disintegrating nicotine tablet, intended useof the orally disintegrating nicotine tablet, etc. The presentapplication gives directions in the examples for the skilled person.

In an embodiment of the invention, the tablet is designed todisintegrate within a period of between 2 and 60 seconds upon oraladministration, such as between 5 and 60 seconds upon oraladministration, such as between 10 and 60 second upon oraladministration.

In an embodiment of the invention, the tablet is designed todisintegrate within a period of less than 45 seconds upon oraladministration.

In an embodiment of the invention, the tablet is designed todisintegrate within a period of between 2 and 45 seconds upon oraladministration, such as between 5 and 45 seconds upon oraladministration, such as between 10 and 45 seconds upon oraladministration.

In an embodiment of the invention, the tablet is designed todisintegrate within a period of less than 30 seconds upon oraladministration.

In an embodiment of the invention, the tablet is designed todisintegrate within a period of between 2 and 30 seconds upon oraladministration, such as between 5 and 30 seconds upon oraladministration, such as between 10 and 30 seconds upon oraladministration.

In an embodiment of the invention, the tablet is designed todisintegrate within a period of less than 20 seconds upon oraladministration, such as between 2 and 20 seconds upon oraladministration, such as between 5 and 20 seconds upon oraladministration, such as between 10 and 20 seconds upon oraladministration.

In an embodiment of the invention, the tablet is designed todisintegrate within a period of less than 15 seconds upon oraladministration, such as between 2 and 15 seconds upon oraladministration, such as between 5 and 15 seconds upon oraladministration, such as between 10 and 15 seconds upon oraladministration.

In an embodiment of the invention, the tablet is designed todisintegrate within a period of between 10 and 25 seconds upon oraladministration.

In an embodiment of the invention, the tablet is designed todisintegrate within a period of between 20 and 40 seconds upon oraladministration.

In an embodiment of the invention, the tablet is designed todisintegrate within a period of between 20 and 60 seconds upon oraladministration.

In an embodiment of the invention, the tablet is designed todisintegrate within a period of between 30 and 60 seconds upon oraladministration.

In an embodiment of the invention, the tablet is designed for thecontent of nicotine to dissolve in the saliva within a period of lessthan 90 seconds upon oral administration.

In the present context dissolving of nicotine has meaning that itdesignates that nicotine upon the disintegration of the tablet isdissolved and thereby available for transport through the mucosa intothe blood stream.

It should be noted that the period of 90 seconds of dissolving of thenicotine upon oral administration reflects that nicotine may dissolveslower than the tablet disintegrates. First of all, it should be notedthat disintegration of the tablet may still involve the presence ofsmaller parts of the tablet and at least that some of the powderparticles are not yet dissolved.

When using nicotine salt(s) as a source of nicotine, it should also benoted that nicotine salts are not necessarily dissolvable in water andthereby in the saliva. It may therefore be preferred to applywater-dissolvable nicotine salts within the scope of the invention.

In an embodiment of the invention, the tablet is designed for thecontent of nicotine to dissolve in the saliva within a period of lessthan 60 seconds upon oral administration.

In an embodiment of the invention, the tablet is designed for thecontent of nicotine to dissolve in the saliva within a period of lessthan 45 seconds upon oral administration.

In an embodiment of the invention, the tablet comprises nicotine in anamount of at least 0.5 mg.

In an embodiment of the invention, the tablet comprises nicotine in anamount of between 0.5 mg to 4 mg.

In an embodiment of the invention, nicotine is provided as a nicotinesalt.

When applying a nicotine salt in the tablet, the resulting amount ofnicotine salt needed to obtain e.g. 1 mg nicotine will be higher,depending on the specific salt, which is why the tablet will be loadedwith an amount of nicotine salt corresponding to the desired amount ofeffective nicotine. For example, when using nicotine bitartrate (nothydrated form), the amount of nicotine bitartrate (not hydrated) neededto obtain 1 mg nicotine is about 2.8 mg.

In an embodiment of the invention, nicotine salt is a water-solublenicotine salt.

The use of a nicotine salt in the present context is to obtain anicotine presence in the nicotine disintegrable tablet, which issuitable as a relatively stable compound in the tablet, but alsooptimized for fast dissolving in the oral cavity.

In the present context, the term “water-soluble salt” is understood as asalt having a solubility in water of at least 10 g of salt per 100 mLwater at standard lab conditions, including temperature of 25 degreesCelsius, atmospheric pressure, and pH of 7.

In an embodiment of the invention, the nicotine salt is selected fromnicotine ascorbate, nicotine aspartate, nicotine benzoate, nicotinemonotartrate, nicotine bitartrate, nicotine chloride (e.g., nicotinehydrochloride and nicotine dihydrochloride), nicotine citrate, nicotinefumarate, nicotine gensitate, nicotine lactate, nicotine mucate,nicotine laurate, nicotine levulinate, nicotine malate, nicotineperchlorate, nicotine pyruvate, nicotine salicylate, nicotine sorbate,nicotine succinate, nicotine zinc chloride, nicotine sulfate, nicotinetosylate and nicotine salt hydrates (e.g., nicotine zinc chloridemonohydrate).

In an embodiment of the invention, the nicotine salt is nicotinebitartrate.

In the present context, nicotine bitartrate includes hydrates thereof.

A specifically suitable nicotine salt applicable within the scope of theinvention is nicotine bitartrate. If using nicotine bitartrate (nothydrated), the preferred amount would be about 1.4 to 11.6 mg as thiswould result in an effective amount of no more than 0.5 to 4 mg ofnicotine in the saliva.

In an embodiment of the invention, nicotine is selected from the groupconsisting of a nicotine salt, the free base form of nicotine, anicotine derivative, such as a nicotine cation exchanger, such asnicotine polacrilex resin, a nicotine inclusion complex or nicotine inany non-covalent binding; nicotine bound to zeolites; nicotine bound tocellulose, such as microcrystalline, or starch microspheres, andmixtures thereof.

In an embodiment of the invention said nicotine is provided as asynthetic nicotine.

An advantage of the above embodiment may be that a more desirable tasteprofile may be obtained by avoiding undesirable taste notes that may beincluded in nicotine obtained from tobacco.

In an embodiment of the invention said nicotine is provided as a complexbetween nicotine and an ion exchange resin.

In an embodiment of the invention said complex between nicotine and theion exchange resin is nicotine polacrilex resin (NPR).

In an embodiment of the invention, the nicotine is provided inassociation with a fatty acid.

In an embodiment of the invention, the fatty acid is oleic acid.

In an embodiment of the invention, the nicotine is provided in ioniccomplex with at least one mucoadhesive water-soluble anionic polymer.

In an embodiment of the invention, the tablet is a sublingual tablet.

When the tablet is a sublingual tablet and when the tablet is used as asublingual tablet, the transfer of nicotine in the mucosa is technicallyextremely advantageous in the sense that even the release rates obtainedthrough the use of the disintegrable tablet results in a very hightransfer of nicotine while affecting the user with much less burningthan should be expected or which has been experienced in any prior artnicotine-delivering tablet. This effect is believed to be due to thefact that burning in the throat affects the user more strongly andmaintains its effect over a longer period of time than when the nicotineis focused on sub-lingual transfer. This is even more advantageous,given the fact that very high concentrations of nicotine may be obtainedsublingually with only minimum burning in the throat. A very highsublingually uptake thus both keeps the burning at a minimum andincreases the nicotine uptake at the same time.

This burning sensation may e.g. be controlled or even reduced whenapplying the nicotine in the tablet in the form as a nicotine salt in anamount of 0.5 mg to 50 mg. The amount of nicotine salt should correspondto an amount of nicotine between 0.5 and 4 mg. The amount of nicotinesalt will therefore depend on the specific nicotine salt applied.

In an embodiment of the invention, the pressed powder comprises at leastone polyol and wherein the polyol comprises more than 40% by weight ofthe tablet.

In an embodiment of the invention, the tablet is pressed at a pressureof 2-20 kN.

According to an embodiment of the invention, the tablet is pressed at apressure of 4-20 kN.

In an embodiment of the invention, the formulation provides a peaksaliva concentration of nicotine of more than 0.3 mg/mL and a peaksaliva pH of more than 8 during the first 120 seconds upon oraladministration.

In an embodiment of the invention, the formulation provides a peaksaliva concentration of nicotine of more than 0.4 mg/mL and a peaksaliva pH of more than 8 during the first 120 seconds upon oraladministration.

In an embodiment of the invention, the formulation provides a peaksaliva concentration of nicotine of more than 0.5 mg/mL and a peaksaliva pH of more than 8 during the first 120 seconds upon oraladministration.

In embodiments where the formulation provides a peak salivaconcentration of nicotine of more than 0.3 mg/mL during the first 120seconds upon oral administration, the amount of nicotine in the tabletshould be adjusted to at least the amount necessary for obtaining this.Depending on the specific formulation, the amount of nicotine in thetablet may be higher than 0.5 mg in some embodiments, such as e.g. atleast 1 mg or at least 2 mg.

In embodiments where the formulation provides a peak salivaconcentration of nicotine of more than 0.5 mg/mL during the first 120seconds upon oral administration, the amount of nicotine in the tabletshould be adjusted to at least the amount necessary for obtaining this.Depending on the specific formulation, the amount of nicotine in thetablet may be higher than 0.5 mg in some embodiments, such as e.g. atleast 1 mg or at least 2 mg.

In an embodiment of the invention, the formulation is designed for thecontent of nicotine to dissolve in the oral saliva within a period ofless than 90 seconds upon oral administration, and wherein at least 40%by weight of the nicotine is absorbed through the oral mucosa.

In an embodiment of the invention, the formulation is designed for thecontent of nicotine to dissolve in the oral saliva within a period ofless than 90 seconds upon oral administration, and wherein at least 50%by weight of the nicotine is absorbed through the oral mucosa.

In an embodiment of the invention, the tablet further comprises adisintegrant.

One advantage of the above embodiment may be that said disintegrantfacilitates the disintegration and dissolution of the tablet, whereby arelease of the nicotine and pH controlling agent is achieved.

In an embodiment of the invention, the disintegrant is selected fromstarch, pregelatinated starch, modified starch (including potato starch,maize starch, starch 1500, sodium starch glycolate and starchderivatives), cellulose, microcrystalline cellulose, alginates,ion-exchange resin, and superdisintegrants, such as crosslinkedcellulose (such as sodium carboxy methyl cellulose), crosslinkedpolyvinyl pyrrolidone (PVP), crosslinked starch, crosslinked alginicacid, natural superdisintegrants, and calcium silicate, and combinationsthereof.

In an embodiment of the invention the disintegrant comprisescross-linked polyvinylpyrrolidone.

In an embodiment of the invention the disintegrant is cross-linkedpolyvinylpyrrolidone.

An advantage of using cross-linked polyvinylpyrrolidone, also known ascrospovidone, as disintegrant, may be that it decreases the dependenceof the disintegration time on the compression force while allowingrather low disintegration times. This may be very preferred especiallyfor fast disintegrating tablets. Also, by being more independent fromcompression force, a lower variation between tablets due to variationsin compression force is facilitated.

In an embodiment of the invention at least 50% by weight of thecross-linked polyvinylpyrrolidone has a particle size below 50micrometers.

This corresponds to commercial grades CL-F and CL-SF.

In an embodiment of the invention at least 25% by weight of thecross-linked polyvinylpyrrolidone has a particle size below 15micrometers.

This corresponds to commercial grade CL-SF.

An advantage of the above embodiment of using cross-linkedpolyvinylpyrrolidone with a smaller particle size facilitates a shorterdisintegration time, e.g. due to a larger relative surface of thedisintegrant particles.

In an embodiment of the invention the tablet comprises disintegrant inan amount of 1-10% by weight of the tablet.

According to an embodiment of the invention, the tablet comprisesdisintegrant in an amount of 2-8% by weight of the tablet, such as 4-6%by weight of the tablet, such as about 5% by weight of the tablet.

Advantageously, the level of disintegrant is high enough to obtain afast disintegration, but not too high as high amounts may increaseproduction costs unnecessarily.

In an embodiment of the invention the tablet comprises sodium stearylfumarate (SSF) as a lubricant.

An advantage of the above embodiment may be that it facilitates ashorter disintegration time of the tablet.

In an embodiment of the invention, the tablet comprises pH regulatingagent in an amount of at least 2.7 percent by weight of said tablet.

According to an embodiment of the invention, the tablet comprises saidpH regulating agent in an amount of between 2.7 and 5.7% by weight ofsaid tablet.

In an embodiment of the invention, the tablet has a weight of 25 to 200mg, such as 50 to 150 mg, such as 70-120 mg, such as about 75 mg orabout 100 mg.

An advantage of the above embodiment may be that it provides a desirablelow disintegration time, while allowing a sufficiently high nicotineamount to be included in the tablet.

In an embodiment of the invention, the tablet comprises microcrystallinecellulose in an amount of 1-10% by weight of the tablet.

An advantage of the above embodiment is that a lower friability may beobtained without compromising the mouthfeel. Including too high amountsof microcrystalline cellulose may lead to a dusty mouthfeel.

According to an embodiment of the invention, the tablet comprisesmicrocrystalline cellulose in an amount of 2-8% by weight of the tablet,such as 4-6% by weight of the tablet, such as about 5% by weight of thetablet.

In an embodiment of the invention, the tablet comprises mannitol as abulk sweetener.

Using mannitol is advantageous due to a lower compactability compared toe.g. sorbitol, isomalt, and xylitol, i.e. for a given compression forcea lower hardness of the tablet is obtained by using mannitol compared tosorbitol, isomalt or xylitol.

In an embodiment of the invention, the tablet comprises a pressed powderformulation, the tablet being designed to disintegrate within a periodof less than 60 seconds upon oral administration, the powder formulationcomprising an amount of nicotine salt and a pH regulating agent andwherein the tablet is designed for the content of nicotine to dissolvein the saliva within a period of less than 90 seconds upon oraladministration.

In an embodiment of the invention, the tablet comprises a pressed powderformulation, the tablet being designed to disintegrate within a periodof less than 60 seconds upon oral administration, the powder formulationcomprising an amount of nicotine salt and a pH regulating agent andwherein the tablet is designed for the content of nicotine to dissolvewithin a period of less than 90 seconds upon oral administration andwherein the nicotine salt is water soluble.

The invention further relates to an orally disintegrating nicotinetablet for use in the alleviation of nicotine craving, comprising apressed powder formulation, the tablet being designed to disintegratewithin a period of less than 60 seconds upon oral administration, thepowder formulation comprising an amount of nicotine and a pH regulatingagent.

In the present context, it should be understood that said use in thealleviation of nicotine craving involves administering said orallydisintegrating nicotine tablet orally.

In an embodiment of the invention, the orally disintegrating nicotinetablet comprises a pressed powder formulation, the tablet being designedto disintegrate within a period of less than 60 seconds upon oraladministration, the powder formulation comprising an amount of nicotinesalt and a pH regulating agent, wherein the tablet wherein the tablet isdesigned for the content of nicotine to dissolve within a period of lessthan 90 seconds upon oral administration.

In an embodiment of the invention the nicotine is not in ionic complexwith a mucoadhesive water-soluble anionic polymer.

In an embodiment of the invention the nicotine does not contain anicotine complex.

According to an embodiment of the invention, the orally disintegratingnicotine tablet for nicotine craving relief comprises a pressed powderformulation, the tablet being designed to disintegrate within a periodof less than 60 seconds upon oral administration, the powder formulationcomprising an amount of nicotine and a pH regulating agent, and whereinthe tablet is designed for the content of nicotine to dissolve in thesaliva within a period of less than 90 seconds upon oral administration.

According to an embodiment of the invention, the orally disintegratingnicotine tablet for nicotine craving relief comprises a pressed powderformulation, the tablet being designed to disintegrate within a periodof less than 60 seconds upon oral administration, the powder formulationcomprising an amount of nicotine and a pH regulating agent, wherein thetablet is designed for the content of nicotine to dissolve in the salivawithin a period of less than 90 seconds upon oral administration andwherein the nicotine is provided as a nicotine salt. This salt shouldpreferably be a water-soluble salt.

In an embodiment of the invention, the orally disintegrating nicotinetablet comprises a pressed powder formulation, the tablet being designedto disintegrate within a period of less than 60 seconds upon oraladministration, the powder formulation comprising an amount of nicotinesalt and a pH regulating agent, wherein the tablet wherein the tablet isdesigned for the content of nicotine to dissolve within a period of lessthan 90 seconds upon oral administration and wherein the tabletcomprises nicotine in an amount of between 0.5 mg to 4 mg.

In an embodiment of the invention, the orally disintegrating nicotinetablet comprises a pressed powder formulation, the tablet being designedto disintegrate within a period of less than 60 seconds upon oraladministration, the powder formulation comprising an amount of nicotinesalt and a pH regulating agent, wherein the tablet wherein the tablet isdesigned for the content of nicotine to dissolve within a period of lessthan 90 seconds upon oral administration, wherein the tablet comprisesnicotine in an amount of between 0.5 mg to 4 mg administration andwherein the nicotine is provided as a nicotine salt. This salt shouldpreferably be a water-soluble salt.

According to an embodiment of the invention, the orally disintegratingnicotine sublingual tablet for nicotine craving relief comprises apressed powder formulation, the tablet being designed to disintegratewithin a period of less than 60 seconds upon oral administration, thepowder formulation comprising an amount of nicotine and a pH regulatingagent, and wherein the tablet is designed for the content of nicotine todissolve in the saliva within a period of less than 90 seconds upon oraladministration.

According to an embodiment of the invention, the orally disintegratingnicotine sublingual tablet for nicotine craving relief comprises apressed powder formulation, the tablet being designed to disintegratewithin a period of less than 60 seconds upon oral administration, thepowder formulation comprising an amount of nicotine and a pH regulatingagent, wherein the tablet is designed for the content of nicotine todissolve in the saliva within a period of less than 90 seconds upon oraladministration and wherein the nicotine is provided as a nicotine salt.This salt should preferably be a water-soluble salt.

In an embodiment of the invention, the orally disintegrating sublingualnicotine tablet comprises a pressed powder formulation, the tablet beingdesigned to disintegrate within a period of less than 60 seconds uponoral administration, the powder formulation comprising an amount ofnicotine salt and a pH regulating agent, wherein the tablet wherein thetablet is designed for the content of nicotine to dissolve within aperiod of less than 90 seconds upon oral administration and wherein thetablet comprises nicotine in an amount of between 0.5 mg to 4 mg.

In an embodiment of the invention, the orally disintegrating sublingualnicotine tablet comprises a pressed powder formulation, the tablet beingdesigned to disintegrate within a period of less than 60 seconds uponoral administration, the powder formulation comprising an amount ofnicotine salt and a pH regulating agent, wherein the tablet wherein thetablet is designed for the content of nicotine to dissolve within aperiod of less than 90 seconds upon oral administration, wherein thetablet comprises nicotine in an amount of between 0.5 mg to 4 mgadministration and wherein the nicotine is provided as a nicotine salt.This salt should preferably be a water-soluble salt.

According to an embodiment of the invention, the orally disintegratingnicotine tablet for nicotine craving relief comprises a pressed powderformulation, the tablet being designed to disintegrate within a periodof less than 60 seconds upon oral administration, the powder formulationcomprising an amount of nicotine and a pH regulating agent, and whereinthe tablet is designed for the content of nicotine to dissolve in thesaliva within a period of less than 90 seconds upon oral administrationand wherein the pressed powder comprises at least one polyol and whereinthe polyol comprises more than 40% by weight of the tablet.

According to an embodiment of the invention, the orally disintegratingnicotine tablet for nicotine craving relief comprises a pressed powderformulation, the tablet being designed to disintegrate within a periodof less than 60 seconds upon oral administration, the powder formulationcomprising an amount of nicotine and a pH regulating agent, wherein thetablet is designed for the content of nicotine to dissolve in the salivawithin a period of less than 90 seconds upon oral administration,wherein the pressed powder comprises at least one polyol and wherein thepolyol comprises more than 40% by weight of the tablet and wherein thenicotine is provided as a nicotine salt. This salt should preferably bea water-soluble salt.

In an embodiment of the invention, the orally disintegrating nicotinetablet comprises a pressed powder formulation, the tablet being designedto disintegrate within a period of less than 60 seconds upon oraladministration, the powder formulation comprising an amount of nicotinesalt and a pH regulating agent, wherein the tablet wherein the tablet isdesigned for the content of nicotine to dissolve within a period of lessthan 90 seconds upon oral administration, wherein the pressed powdercomprises at least one polyol and wherein the polyol comprises more than40% by weight of the tablet and wherein the tablet comprises nicotine inan amount of between 0.5 mg to 4 mg.

In an embodiment of the invention, the orally disintegrating nicotinetablet comprises a pressed powder formulation, the tablet being designedto disintegrate within a period of less than 60 seconds upon oraladministration, the powder formulation comprising an amount of nicotinesalt and a pH regulating agent, wherein the tablet wherein the tablet isdesigned for the content of nicotine to dissolve within a period of lessthan 90 seconds upon oral administration, wherein the pressed powdercomprises at least one polyol and wherein the polyol comprises more than40% by weight of the tablet and wherein the tablet comprises nicotine inan amount of between 0.5 mg to 4 mg administration and wherein thenicotine is provided as a nicotine salt. This salt should preferably bea water-soluble salt.

Moreover the invention relates to a method of alleviation of nicotinecraving by administering an effective amount of said orallydisintegrating nicotine tablet according to the invention or any of itsembodiments.

DETAILED DESCRIPTION

As used herein, the term “orally disintegrating tablet” refers to atablet for oral administering which disintegrates in the oral cavityrelatively fast from the administering, such as within about threeminutes from oral administering. Orally disintegrating tablets may beintended for use as a sublingual tablet for positioning under thetongue, as a buccal tablet, as a tablet for melting on the tongue, orfor other types of oral administering.

Orally disintegrating tablets may also be referred to “orally dissolvingtablets”, and these two terms are used interchangeably herein. Commonly,these terms are also referred to by their abbreviation, ODT. Similarly,the terms “fast dissolving tablet” and “fast disintegrating tablet”, aswell as the abbreviation FDT, refers herein to an orally disintegratingtablet.

As used herein, the term “disintegrate” refers to a reduction of a saidobject to components, fragments or particles. Disintegration time ismeasured in vitro. The in vitro measurements are carried out inaccordance to European Pharmacopeia 9.0, section 2.9.1, Disintegrationof tablets and capsules.

As used herein, the term “dissolve” is the process where a solidsubstance enters a solvent (oral saliva) to yield a solution. Unlessotherwise stated, dissolving implies a full dissolving of the compoundin question.

As used herein, the terms “disintegrant” refers to an ingredientfacilitating disintegration of an orally disintegrating tablet, when theorally disintegrating tablet comes into contact with saliva.Disintegrants usable within the scope of the invention may includestarch, pregelatinated starch, modified starch (including potato starch,maize starch, starch 1500, sodium starch glycolate and starchderivatives), cellulose, microcrystalline cellulose, alginates,ion-exchange resin, and superdisintegrants, such as crosslinkedcellulose (such as sodium carboxy methyl cellulose), crosslinkedpolyvinyl pyrrolidone (PVP), crosslinked starch, crosslinked alginicacid, natural superdisintegrants, and calcium silicate. Disintegrantsmay often be considered as measure promoting the break-up of the dosageform into smaller fragments upon administration to allow the onset ofdrug dissolution and eventual absorption.

As used herein, the term “nicotine” refers to nicotine in any form,including free base nicotine, nicotine salts, nicotine bound to ionexchange resins, such as nicotine polacrilex, nicotine bound tozeolites; nicotine bound to cellulose, such as microcrystallinecellulose, such as of microbial origin, or starch microspheres, nicotinebound to CaCO3, and mixtures thereof. Thus, when referring to nicotineamounts, the amounts refers to the amount of pure nicotine. Thus, whenmeasuring the concentration of nicotine added as nicotine salt, it isthe mass of the equivalent amount of pure nicotine, not the mass of thesalt, that is relevant. Nicotine also covers nicotine not obtained fromtobacco, often referred to as synthetic nicotine.

As used herein, the term “nicotine salt” refers to nicotine in ionizedform bonded electrostatically to a counterion.

As used herein, the term “NBT” refers to nicotine bitartrate andhydrates thereof.

As used herein, the term “%” and “percent” refers to percent by weight,unless otherwise is stated.

As used herein, the term “release of nicotine” refers to the nicotinebeing made bioavailable, i.e. available for absorption over the mucousmembrane in the oral cavity. While some forms of nicotine requiredissolution for being bioavailable, other forms may be readily absorbedinto the body without dissolution. For example, in order for thenicotine to be bioavailable, the matrix of the solid formulation shouldbe disintegrated. Some forms of nicotine require the nicotine to furtherbe released from e.g. a carrier, e.g. nicotine from a nicotine-ionexchange resin such as nicotine polacrilex. Other nicotine forms, suchnicotine salts, hereunder nicotine bitartrate, may readily dissolve upondisintegration of the matrix of the solid formulation. Still, somenicotine forms may not require dissolving. This applies for e.g.nicotine free base, which is released upon disintegration of the solidformulation matrix.

As used herein, the term “peak saliva concentration of nicotine” refersto the peak value of the concentration of nicotine in saliva of the oralcavity, where the saliva includes delivery vehicle of the nicotinedissolved therein. Also, it should be understood that the peak salivaconcentration is considered to be achieved whenever the criterion isfulfilled. E.g. if a peak saliva concentration of nicotine is at least0.5 mg/mL, this peak saliva concentration is achieved whenever theconcentration of nicotine exceeds 0.5 mg/mL. Measurements of peak salivanicotine concentration is performed as follows:

One dosage of the tablet is administered sublingually to at least sixindividuals. At specified time intervals, the saliva is collected. Theexperiment is repeated. Thus, each nicotine concentration value is thearithmetic mean of 12 measurements, i.e. performed on saliva-samplesfrom six individuals times 2. The nicotine concentration of saliva isanalyzed on HPLC after extraction into relevant buffer.

As used herein, the term “peak saliva pH” refers to the peak value ofthe pH in saliva of the oral cavity, where the saliva includes anydelivery vehicle of the pH regulating agent. Also, it should beunderstood that the peak saliva pH is considered to be achieved wheneverthe criterion is fulfilled. E.g. if a peak saliva pH is at least 7.5,this peak saliva pH is achieved whenever the pH exceeds 7.5. Peak salivapH is measured in vivo and is measured as follows:

At least 6 individuals chewed on a gum base free of buffer for 1 minute,after which the initial pH in a sample from the saliva from each of theindividuals is measured with a suitable pH-electrode system, e.g. astainless steel electrode PHW77-SS. Only individuals having, afterchewing on a gum base free of buffer for one minute, an initial pH inthe saliva inside the range from 6.7 and 7.3 are selected. Theseindividuals thereby qualify as average individuals.

One dosage of the tablet is administered sublingually to at least sixindividuals. Hereafter, the saliva pH from each of the six individualsis measured at specified time intervals. Thus, each pH-value is thearithmetic mean of six measurements performed on saliva-samples from sixindividuals.

As used herein, the term “pH regulating agent” refers to agents, whichactive adjust and regulates the pH value of the solution to which theyhave been added or are to be added. Thus, pH regulating agents may beacids and bases, including acidic buffering agents and alkalinebuffering agents. On the other hand, pH regulating agents does notincluding substances and compositions that can only affect the pH bydilution. Furthermore, pH regulating agents does not include e.g.flavoring, fillers, etc.

As used herein, the term “buffering agent” is used interchangeably with“buffer” and refers to agents for obtaining a buffer solution. Bufferingagents include acidic buffering agents, i.e. for obtaining a buffersolution with an acidic pH, and alkaline buffering agents, i.e. forobtaining a buffer solution with an alkaline pH.

As used herein, the term “fast onset nicotine craving relief” refers torelief of nicotine craving, for which the onset is relatively fast, i.e.only a relatively short period of time after oral administering. Inembodiments of the invention, the fast onset refers to a period afteroral administration until craving relief is experienced being no morethan 180 seconds, such as no more than 120 seconds, such as no more than60 seconds.

EXAMPLES

The following non-limiting examples illustrate different variations ofthe present invention.

Example 1

Preparation of Fast Disintegrating Tablet

In the present example six fast disintegrating tablets (FDT) with 1 mgnicotine are prepared with formulations as outlined in table 1. The fastdisintegrating tablet is prepared with NBT (nicotine bitartratedihydrate). Punch used: 7.00 mm, circular, shallow concave, D tooling.Tablet weight: 100.0 mg.

TABLE 1 Fast disintegrating tablet compositions. FDT(a) FDT(b) FDT(c)FDT(d) FDT(e) FDT(f) NBT 2.849 2.849 2.849 2.849 2.849 2.849 Micro- — —— 40.175 40.175 40.175 crystalline cellulose Mannitol 81.351 81.35181.351 40.175 40.175 40.175 Crospovidone 5.0 — — 5.0 — — Croscarmellose— 5.0 — — 5.0 — Sodium Sodium Starch — — 5.0 — — 5.0 GlycolatePeppermint 4.0 4.0 4.0 4.0 4.0 4.0 Menthol 0.4 0.4 0.4 0.4 0.4 0.4Sucralose 0.4 0.4 0.4 0.4 0.4 0.4 Sodium 5.0 5.0 5.0 5.0 5.0 5.0carbonate Silicium — — — 1.0 1.0 1.0 dioxide Magnesium 1.0 1.0 1.0 1.01.0 1.0 stearate Total 100.0 100.0 100.0 100.0 100.0 100.0 Amounts aregiven in mg. FDT = Fast disintegrating tablet.

Raw materials are weighed from bags or buckets into separate weighingcontainers. All excipients are sifted through an 800 micrometer sieveinto a stainless steel or plastic bin in the following order:

-   -   Half the filler/bulk sweetener    -   The API and all other excipients, except magnesium stearate    -   The remaining half of the filler/bulk sweetener

These are mixed in a Turbula mixer for 4-10 minutes at 25 RPM. Thenlubricant, for example magnesium stearate is sifted through an 800micrometer sieve into the mixing bin, and the lubrication is conductedby additional mixing for 1-2 minutes at 25 RPM. The fill level of themixing bin is kept between 40% and 70%, according to standardizedpractice. The lubricated powder blend is transferred to the hopper of atableting machine.

The fast disintegrating tablets are manufactured on a lab scale machine,for example RIVA Piccola bi-layer tablet press. The tablet machine iscommissioned by adjusting the fill depth and compression force so theweight and hardness of lozenges match the acceptance criteria. Apre-compression force could be included to avoid capping.

TABLE 2 Suggested start up parameters. Parameter Target value Speed10-20 rpm Weight of FDT 100 mg +/− 5% Compression force 2-8 kN ThicknessN/A* Friability (100 rpm) <1% *The design of punches is not fixed. Asthe curvature impacts thickness, the thickness is not a fixed target atthis time of development.

The acceptance criteria for friability should be fulfilled so packagingof the resulting fast disintegrating tablets is possible, but in thisembodiment, the bulk sweetener and or filler should have relatively goodcompressibility and still have fast disintegration. The fastdisintegrating tablets according to the invention may comprise coloringagents. According to an embodiment of the invention, the fastdisintegrating tablets may comprise color agents and whiteners such asFD&C-type dyes and lakes, fruit and vegetable extracts, titanium dioxideand combinations thereof.

Example 2

Preparation of Fast Disintegrating Tablet Using Ready to Use Systems

Another way of preparing fast disintegrating tablets would be to use aready to use system. Suitable for the purpose could be but not limitedto: Pearlitol Flash (Roquette), Pharmaburst 500 (SPI Pharma), Ludiflash(BASF), ProSolv (JRS Pharma), ProSolv EasyTab (JRS Pharma), F-Melt (FujiChemical), SmartEx50 or SmartEx100 (Shin Etsu/Harke Pharma). These readyto use systems co-processed systems where filler, disintegrant, glidantor similar are implemented in the one powder mix. This saves handling ofseveral excipients and ensures homogeneity between excipients.

In the present example five fast disintegrating tablets (FDT(g)-FDT(k))without nicotine are prepared with ready to use systems in formulationsas outlined in table 3A. The fast disintegrating tablet is preparedwithout NBT (placebo). Adding nicotine to the fast disintegratingtablets is expected to influence disintegration time onlyinsignificantly.

In this example, the following conditions where applied. Punch used:7.00 mm, circular, shallow concave, B tooling. Tablet weight: 100.0 mg.

TABLE 3A Fast disintegrating tablet compositions with different ready touse systems. Amounts are given in mg. FDT = Fast disintegrating tablet.FDT(g) FDT(h) FDT(i) FDT(j) FDT(k) Ludiflash 81.7  — — — — PearlitolFlash — 81.7  — — — SmartEx QD50 — — 81.7  — — F-Melt — — — 83.7  —ProSolv ODT G2 — — — — 83.7  Peppermint 4.4 4.4 4.4 4.4 4.4 Menthol 1.51.5 1.5 1.5 1.5 Sucralose 0.4 0.4 0.4 0.4 0.4 Sodium carbonate 5.0 5.05.0 5.0 5.0 Crospovidone 5.0 5.0 5.0 — — Croscarmellose Sodium — — — 3.0— Sodium Starch Glycolate — — — — 3.0 Magnesium stearate 2.0 2.0 2.0 2.02.0 Total 100.0  100.0  100.0  100.0  100.0 

Additionally, five fast disintegrating tables (FDT(1)-FDT(p)) withnicotine are prepared with ready to use systems in formulations asoutlined in table 3B.

In this example, the following conditions where applied. Punch used:7.00 mm, circular, shallow concave, B tooling. Tablet weight: 100.0 mg.

TABLE 3B Fast disintegrating tablet compositions with different ready touse systems and nicotine as nicotine bitartrate, NBT or nicotinepolacrilex, NPR (15% nicotine load). Amounts are given in mg. FDT = Fastdisintegrating tablet. FDT(l) FDT(m) FDT(n) FDT(o) FDT(p) NBT — — 3.03.0 3.0 NPR 6.7 6.7 — — — Ludiflash 75.0  — — — — Pearlitol Flash —75.0  — — — SmartEx QD50 — — 78.7  — — F-Melt — — — 80.7  — ProSolv ODTG2 — — — — 80.7  Peppermint 4.4 4.4 4.4 4.4 4.4 Menthol 1.5 1.5 1.5 1.51.5 Sucralose 0.4 0.4 0.4 0.4 0.4 Sodium carbonate 5.0 5.0 5.0 5.0 5.0Crospovidone 5.0 5.0 5.0 — — Croscarmellose Sodium — — — 3.0 — SodiumStarch Glycolate — — — — 3.0 Magnesium stearate 2.0 2.0 2.0 2.0 2.0Total 100.0  100.0  100.0  100.0  100.0 

Further four fast disintegrating tablets (FDT(1)-FDT(4)) with nicotineare prepared with varying amounts of MCC (microcrystalline cellulose) asfiller, as outlined in table 3C.

In this example, the following conditions where applied. Punch used:7.00 mm, circular, shallow concave, B tooling. Tablet weight: 100.0 mg.

TABLE 3C Fast disintegrating tablet compositions with varying amounts ofMCC and nicotine (1 mg/tablet) sorbed onto calcium carbonate, (syntheticfree nicotine base sorted onto calcium carbonate in a weight ratio of1:2). Amounts are given in mg. FDT = Fast disintegrating tablet. FDT(1)FDT(2) FDT(3) FDT(4) Nicotine-calcium carbonate 3.0 3.0 3.0 3.0Microcrystalline cellulose 0.0 5.0 10.0 20.0 Mannitol 79.7 74.7 69.759.7 Crospovidone 5.0 5.0 5.0 5.0 Peppermint 4.4 4.4 4.4 4.4 Menthol 1.51.5 1.5 1.5 Sucralose 0.4 0.4 0.4 0.4 Sodium carbonate 5.0 5.0 5.0 5.0Magnesium stearate 1.0 1.0 1.0 1.0 Total 100.0 100.0 100.0 100.0

Four fast disintegrating tablets, FDT(5)-FDT(8), with nicotine areprepared with varying amounts of disintegrant, as outlined in table 3D.

In this example, the following conditions where applied. Punch used:7.00 mm, circular, shallow concave, B tooling. Tablet weight: 100.0 mg.

TABLE 3D Fast disintegrating tablet compositions with varying amount ofdisintegrant. Amounts are given in mg. FDT = Fast disintegrating tablet.FDT(5) FDT(6) FDT(7) FDT(8) NBT 3.0 3.0 3.0 3.0 Mannitol 41.7 39.2 41.731.7 Microcrystalline cellulose 43 43 43 43 Crospovidone 0.0 2.5 5.0-10.0 Peppermint 4.4 4.4 4.4 4.4 Menthol 1.5 1.5 1.5 1.5 Sucralose 0.40.4 0.4 0.4 Sodium carbonate 5.0 5.0 5.0 5.0 Magnesium stearate 1.0 1.01.0 1.0 Total 100.0 100.0 100.0 100.0

Three fast disintegrating tablets, FDT(9)-FDT(11), with nicotine areprepared with varying types of lubricants, as outlined in table 3E.

In this example, the following conditions where applied. Punch used:7.00 mm, circular, shallow concave, B tooling. Tablet weight: 100.0 mg.

TABLE 3E Fast disintegrating tablet compositions. Amounts are given inmg. FDT = Fast disintegrating tablet. FDT(9) FDT(10) FDT(11) NBT 3.0 3.03.0 Microcrystalline cellulose 5 5 5 Mannitol 78.6 77.6 77.6Crospovidone 5.0 5.0 5.0 Eucamenthol Flavour 2 2 2 Sucralose 0.4 0.4 0.4Sodium carbonate 5.0 5.0 5.0 Magnesium stearate 1.0 — — Sodium stearylfumarate — 2.0 — Compritol HD5 — — 2.0 Total 100.0 100.0 100.0

Three fast disintegrating tablets, FDT(12)-FDT(14), with nicotine areprepared, as outlined in table 3F.

In this example, the following conditions where applied. Punch used:7.00 mm, circular, shallow concave, B tooling. Tablet weight: 75.0 mg.

TABLE 3F Fast disintegrating tablet compositions. Amounts are given inmg. FDT = Fast disintegrating tablet. FDT(13) was made similar toFDT(12) but without buffer. FDT(14) was made similar to FDT(12) butwithout disintegrant. FDT(12) FDT(13) FDT(14) SmartEx QD 50 60.0 65.065.0 Nicotine Bitartrate (NBT) 3.0 3.0 3.0 Sodium carbonate anhydrous5.0 0.0 5.0 Crospovidone (Kollidon CL-F, 5.0 5.0 0.0 BASF) PeppermintPowder 0.4 0.4 0.4 Sucralose 0.4 0.4 0.4 Aerosil 200 (silicium dioxide)0.2 0.2 0.2 Magnesium Stearate 1.0 1.0 1.0 Total 75.0 75.0 75.0

FDT(12)-FDT(13) were pressed to a hardness of 15-20 N. FDT (14) waspressed to a hardness of 25-35 N.

As described below, the tablets may be made from a wide range ofdifferent formulations.

As can be seen in table 1, microcrystalline cellulose is used as afiller. Lower amount of filler such as microcrystalline cellulose mayalso be used. Examples of usable fillers include magnesium- and calciumcarbonate, sodium sulphate, ground limestone, silicate compounds such asmagnesium- and aluminum silicate, kaolin and clay, aluminum oxide,silicium oxide, talc, titanium oxide, mono-, di- and tri-calciumphosphates, cellulose polymers, such as wood, starch polymers, fibersand combinations thereof.

As can be seen in table 1, mannitol is used as a bulk sweetener.Examples of usable bulk sweeteners include sugar sweetener and/orsugarless sweetener.

The bulk sweeteners may often support the flavor profile of theformulation.

Sugar sweeteners generally include, but are not limited tosaccharide-containing components, such as sucrose, dextrose, maltose,saccharose, lactose, sorbose, dextrin, trehalose, D-tagatose, driedinvert sugar, fructose, levulose, galactose, corn syrup solids, glucosesyrup, hydrogenated glucose syrup, and the like, alone or incombination. These sugar sweeteners may also be included as a humectant.

Sugarless sweeteners generally include, but are not limited to sugaralcohols (also sometimes referred to as polyols) such as sorbitol,erythritol, xylitol, maltitol, mannitol, lactitol, and isomalt.

As can be seen in table 1 and 3A-3F, crospovidone, croscarmellosesodium, and sodium starch glycolate are used as disintegrants. Examplesof usable disintegrants include starch, pregelatinated starch, modifiedstarch (including potato starch, maize starch, starch 1500, sodiumstarch glycolate and starch derivatives), cellulose, microcrystallinecellulose, alginates, ion-exchange resin, and superdisintegrants, suchas crosslinked cellulose (such as sodium carboxy methyl cellulose),crosslinked polyvinyl pyrrolidone (PVP), crosslinked starch, crosslinkedalginic acid, natural superdisintegrants, and calcium silicate, andcombinations thereof.

As can be seen in table 1 and 3A-3F, sucralose is used as a highintensity sweetener. Usable high intensity sweeteners include, but arenot limited to sucralose, aspartame, salts of acesulfame, such asacesulfame potassium, alitame, saccharin and its salts, cyclamic acidand its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin,stevioside and the like, alone or in combination.

As can be seen in table 1 and 3A-3F, peppermint and menthol are used asflavors. Usable flavors include almond, almond amaretto, apple, Bavariancream, black cherry, black sesame seed, blueberry, brown sugar,bubblegum, butterscotch, cappuccino, caramel, caramel cappuccino,cheesecake (graham crust), cinnamon redhots, cotton candy, circus cottoncandy, clove, coconut, coffee, clear coffee, double chocolate, energycow, graham cracker, grape juice, green apple, Hawaiian Punch®, honey,Jamaican rum, Kentucky bourbon, kiwi, koolada, lemon, lemon lime,tobacco, maple syrup, maraschino cherry, marshmallow, menthol, milkchocolate, mocha, Mountain Dew®, peanut butter, pecan, peppermint,raspberry, banana, ripe banana, root beer, RY 4, spearmint, strawberry,sweet cream, sweet tarts, sweetener, toasted almond, tobacco, tobaccoblend, vanilla bean ice cream, vanilla cupcake, vanilla swirl, vanillin,waffle, Belgian waffle, watermelon, whipped cream, white chocolate,wintergreen, amaretto, banana cream, black walnut, blackberry, butter,butter rum, cherry, chocolate hazelnut, cinnamon roll, cola, creme dementhe, eggnog, English toffee, guava, lemonade, licorice, maple, mintchocolate chip, orange cream, peach, pina colada, pineapple, plum,pomegranate, pralines and cream, red licorice, salt water taffy,strawberry banana, strawberry kiwi, tropical punch, tutti frutti,vanilla, or any combination thereof.

According to an embodiment of the invention, flavor may be used as tastemasking for the nicotine.

In some embodiments of the invention, the formulation comprises pHregulating agent.

In some embodiments of the invention, the formulation comprises pHregulating agent in an amount of 2.7 to 5.7% by weight of saidformulation.

In some embodiments of the invention, the pH regulating agent comprisesbuffer.

As can be seen in table 1 and 3A-3F, sodium carbonate is used as abuffering agent. Usable buffering agents include carbonate, includingmonocarbonate, bicarbonate and sesquicarbonate, glycerinate, phosphate,glycerophosphate, acetate, glyconate or citrate of an alkali metal,ammonium, tris buffer, amino acids and mixtures thereof. Encapsulatedbuffer such as Effersoda may also be used.

In some embodiments, the formulation comprises buffering agent in anamount of from 2.7 to 5.7% by weight of the formulation.

The buffering agent may be added to the formulation together with thewater-soluble fast disintegrating tablet ingredients.

When buffering agent is added to the fast disintegrating tablet as partof the water-soluble fast disintegrating tablet ingredients, apH-profile according to embodiments of the present invention can beobtained.

Buffering agent in the tablet may be used to obtain the desiredpH-values in the saliva of a tablet user.

In some embodiments, the buffering agent comprises sodium carbonate andsodium bicarbonate, e.g. in a weight-ratio between 5:1 and 2.5:1,preferably in a weight-ratio between 4.1:1 and 3.5:1.

A high suitable buffering agent according to advantageous embodiments ofthe present invention is the sodium carbonate-sodium bicarbonate buffersystem.

As can be seen in table 1, silicon dioxide is used as a glidant. Otherglidants usable for the formulation may also be used within the scope ofthe invention.

As can be seen in table 1 and 3A-3F, magnesium stearate is used as alubricant. Other lubricants usable for the formulation may also be usedwithin the scope of the invention.

As can be seen in table 3A-3F, ready to use systems may be used.Typically, such ready-to-use systems may e.g. replace filler,disintegrant, glidant or similar with a single powder mix. Suitableready-to-use systems for the purpose, but not limited to, includePearlitol Flash (Roquette), Pharmaburst 500 (SPI Pharma), Ludiflash(BASF), ProSolv (JRS Pharma), ProSolv EasyTab (JRS Pharma), F-Melt (FujiChemical), SmartEx50 or SmartEx100 (Shin Etsu/Harke Pharma).

In order to obtain a tablet being designed for disintegrating within aperiod of 60 second upon oral administration, a range of parameters canbe adjusted.

First, by varying the composition, the disintegration time can bealtered. Using ingredients with a high water-solubility may facilitate alowered disintegration time.

Particularly, including a disintegrant may significantly influence thedisintegration time, subject to the total composition. Also, by varyingthe amount and type of the disintegrant, the disintegration time may befurther adjusted. For example, if a tablet having a lower disintegrationtime is desired, the percentage content of disintegrant may be increasedand/or the type of disintegrant may be at least partly exchanged for amore effective disintegrant.

Also, decreasing the particle size of the disintegrant tends to lowerthe disintegration time, likely due to an increased surface area tovolume ratio.

Furthermore, the compression force used in compressed tablets correlatesignificantly with the obtained hardness, such that a high compressionforce typically increases the hardness of the obtained tablet. Byadjusting the hardness of a tablet, the disintegration time may also beinfluenced, such that a lowered hardness typically gives a shorterdisintegration time. Here it has been observed for a number ofcompositions that by applying the correct compression force adisintegration time below 60 second upon oral administration can beachieved, whereas a too high compression force may result in a longerdisintegration time above 60 seconds. In this regard it is noted thatthe threshold compression force may vary significantly, depending onother parameters, such as overall composition, content and type ofdisintegrant, etc. When, for example, a certain setup results in a tooslow disintegration, a further way of adjusting may be to replace aregular disintegrant with a superdisintegrant, i.e. which facilitatesdisintegration in a more efficient way.

Increasing the water-solubility may also be facilitated by exchangingingredients with low water-solubility with ingredients having higherwater-solubility. For example, using sugar alcohols as fillers may bevery advantageous insofar that the sugar alcohols have a higher watersolubility than alternative fillers.

Moreover, using sugar alcohols with a lower compactibility leads tolower disintegration time. Too low compactibility may compromise themechanical strength of the tablet and lead to undesirably highfriability and risk of cracks etc.

Further examples of parameters that may be adjusted in order to obtain atablet being designed for disintegrating within a period of 60 secondupon oral administration include size and shape of the tablet. Thelarger the tablet, the longer the disintegration time and thus releasetime of the nicotine and pH regulating agent.

For example, increasing the flatness (e.g. quantified by a diameter toheight ratio) for a disc-shaped tablet typically increasesdisintegration time by increasing the surface-to-volume. As long as thetablet has a satisfactory mechanical strength, flatness may beincreased.

Also, modifying the cross-sectional profile from a convex type tablet toa concave shaped tablet lowers the disintegration time. It is noted thatthis may to some degree lower the mechanical strength of the tablet,however, as long as it is satisfactory, pursuing the concavecross-section may help to increase disintegration and thus lower thedisintegration time.

Also, when using binders, e.g. to obtain a higher cohesiveness andmechanical strength of the tablet, the amount of such binders may bedecreased as much as possible to obtain a higher disintegration rate andthus a shorter disintegration time.

Furthermore, by adding a salivation agent to the tablet, an increasedamount of saliva in the vicinity of the tablet may be facilitated, whichagain supports the dissolving and disintegration of the tablet to reducethe disintegration time.

Further, the type and amount of lubricant, if any, may be adjusted tooptimize disintegration time. For example, using Sodium stearyl fumarate(SSF) typically leads to a lower disintegration time compared to whenusing magnesium stearate MgSt.

Thus, a wide range of parameters may be adjusted when designing a tabletdesigned for disintegrating within a period of 60 second upon oraladministration.

Typically, the formulation comprises of ingredients selected from thegroup consisting of bulk sweeteners, fillers, ready to use systems,flavors, dry-binders, disintegrant, hereunder superdisintegrants,tabletting aids, anti-caking agents, emulsifiers, antioxidants,enhancers, absorption enhancers, buffering agents, high intensitysweeteners, colors, glidants, lubricants, or any combination thereof.Absorption enhancers may include e.g. pH regulating agents, such asbuffering agents, and mucoadhesive.

In an embodiment of the invention, the tablet core is provided with anouter coating.

In an embodiment of the invention, said outer coating is selected fromthe group consisting of hard coating, soft coating and ediblefilm-coating or any combination thereof.

According to an embodiment of the invention, at least a part of thenicotine is adhered to dry-binder particles.

According to an embodiment of the invention, an amount of dry-binder isused to adhere nicotine to bulk sweetener.

According to an embodiment of the invention, said fast disintegratingtablet comprises one or more encapsulation delivery systems.

Example 3

In Vivo pH

The fast disintegrating tablets are designed to have an in vivo pHhigher than the resting saliva pH in the mouth. Thus, pH is measured invivo, as follows:

At least 6 individuals chewed on a gum base free of buffer for 1 minute,after which the initial pH in a sample from the saliva from each of theindividuals is measured with a suitable pH-electrode system, e.g. astainless-steel electrode PHW77-SS. Only individuals having, afterchewing on a gum base free of buffer for one minute, an initial pH inthe saliva inside the range from 6.7 and 7.3 are selected. Theseindividuals thereby qualify as average individuals.

One tablet is administered sublingually to at least six individuals.Hereafter, the saliva pH from each of the six individuals is measured atspecified time intervals. Thus, each pH-value is the arithmetic mean ofsix measurements performed on saliva-samples from six individuals.

The sample volume of the individual saliva-samples may vary because thevolume of saliva obtained may be different from each individual. Thisdifference in sample volume does not affect the pH-measurementssignificantly. Also, it has been established by appropriate tests that avariation in time between collections of samples does not significantlyalter the result. This means that the measured pH-value after threeminutes is not significantly affected by whether another saliva-sampleis taken from the six individuals e.g. after two minutes or not.Furthermore, it has been established by appropriate tests that the timefrom taking a sample to the time of measuring is not critical to themeasured value. However, in the present measurements, the pH-values weremeasured in the samples within at most 15 minutes of sample collection.

The results are shown in table 3G.

TABLE 3G In vivo pH. Nicorette Microtab (2 mg), Nicotinell Mint Lozenge(2 mg), and Nicotinell Mint Chewing gum (2 mg) were commerciallyavailable products. pH 10 sec 20 sec 90 sec DT (sec) FDT (12) (1 mg) 9.39.1 8.4 20 FDT (14) (1 mg) 7.4 7.2 7.6 210 FDT (13) (1 mg) 5.3 5.8 6.515 Nicorette Microtab (2 mg) 6.7 6.8 6.8 >600 Nicotinell Mint Lozenge (2mg) 6.9 7.1 7.2 >600 Nicotinell Mint Chewing gum 7.2 7.4 7.6 NA (2 mg)

As can be seen from table 3G, the pH exceeds 7.5 for FDT 12 and 13. ForFDT 12, this even applies already at 10 and 20 seconds from contact withoral saliva. FDT(13), made without any buffer, did not give a pH above7.5.

The needed rise in saliva pH is at least 0.5-1.0 pH units. Aconventional nicotine mouth spray was chosen for comparison as well asNicorette Microtab, Nicotinell Mint Lozenge, and Nicotinell Mint chewinggum. The conventional nicotine mouth spray reveals also fast cravingrelief. The conventional nicotine mouth spray raises the pH in saliva upto a maximum of 8.5 according to internal measurements. None ofNicorette Microtab and Nicotinell Mint Lozenge resulted in pH above 7.2.Nicotinell Mint chewing gum did not result in pH above 7.6.

The sample volume of the individual saliva-samples may vary because thevolume of saliva obtained may be different from each individual. Thisdifference in sample volume does not affect the pH-measurementssignificantly.

It should be noted that the in vivo pH would be different from an invitro pH due to the fact that acidic sodium bicarbonate is normallycontinuously produced in saliva, hence neutralizing the alkalinecontribution from buffer. Thus, the pH obtained in vivo will be lowerthan in vitro measured by e.g. dissolving the tablet in a beaker.

Example 4

Disintegration of Nicotine Tablets

The in vitro disintegration of the fast disintegrating tablets ofexample 1 and 2 was carried out in accordance to European Pharmacopeia9.0, section 2.9.1, Disintegration of tablets and capsules. As describedin the examples each batch has been manufactured in various tablet sublots where the compression force has been varied and therefore theoutput parameters like hardness and friability will also vary. Theseoutput parameters do also have an impact on in vitro disintegration. Theresults for example 1 are outlined in table 4. A minimum and a maximumvalue for measured disintegration are given and this is more or less afunction of the hardness.

TABLE 4 In vitro disintegration, hardness, friability. Time is given inseconds. Mean in vitro disintegration Mean hardness Mean friability(sec) (N) (%) Min Max Min Max Min Max (sec) (sec) (N) (N) (%) (%) FDT(a)21 24 14 63 0.0 0.3 FDT(b) 23 98 12 50 0.0 0.6 FDT(c) 29 177 14 55 0.00.5 FDT(d) 15 177 19 62 0.0 0.0 FDT(e) 13 175 15 45 0.0 0.2 FDT(f) 11259 14 43 0.0 0.2

The above table should be interpreted as illustrated in the followingexample. When looking at e.g. FDT(a), the minimum mean disintegrationtime of 21 seconds correspond to a tablet pressed just hard enough toobtain a cohesive tablet having a minimum mean hardness of 14 N and afriability of 0.3%. Similarly, the maximum mean disintegration time of24 seconds correspond to another tablet pressed harder to have a maximummean hardness of 63 N. In this way, the tablet having a mean friabilityof 0.0% of FDT(a) corresponds to the tablet having a mean hardness of 63N. In other words, in table 4 FDT(a) refers to two different tabletspressed at two different pressures, the linking being indicated above.I.e. each line corresponds to two different tablets, one for Min valuesof disintegration time and hardness and the Max value for friability,and another for Max values of disintegration time and hardness and theMin value for friability.

The results for example 2 are outlined in table 5.

TABLE 5 In vitro disintegration, hardness, friability. Time is given inseconds. Mean in vitro disintegration Mean hardness Mean friability(sec) (N) (%) Min Max Min Max Min Max (sec) (sec) (N) (N) (%) (%) FDT(g)120 210 17 22 N/A 0.5 FDT(h) 40 80 16 24 0.5 0.8 FDT(i) 10 46 17 22 0.30.3 FDT(j) 42 150 17 22 0.7 1.0 FDT(k) 45 201 17 22 0.6 0.9

The above table should be interpreted as illustrated in the examplebelow table 4.

It is seen that the in vitro disintegrating may vary a lot between thedisclosed fast disintegrating tablets. Hereby a disintegration profileas desired may be used together with a high in vivo pH (as described inexample 3), whereby the nicotine may be more efficiently used. Mostpreferable an in vitro disintegrating profile below 60 seconds isdesired since it would ensure a high concentration of nicotine combinedwith relatively high in vivo pH.

The in vitro disintegration is a fast method to determine the time andmechanism for tablet performance. More preferable or in combination thein vivo disintegration is measured. The in vivo disintegration time is avalue for the actual disintegration of the sublingual tablet under thetongue. Table 6 and 7 highlights the results for in vivo disintegration.

TABLE 6 In vivo disintegration. Time is given in seconds. Mean in vivodisintegration (sec) Min (sec) Max (sec) FDT(a) 34 52 FDT(b) 18 27FDT(c) 37 N/A FDT(d) 42 N/A FDT(e) 46 N/A

TABLE 7 In vivo disintegration. Time is given in seconds. Mean in vivodisintegration (sec) Min (sec) Max (sec) FDT(g) 19 40 FDT(h) 13 48FDT(i) 32 80 FDT(j) N/A 56 FDT(k) N/A 81

The above tables 6-7 should be interpreted as illustrated in the examplebelow table 4.

As recognized for the in vitro disintegration results above the speed ofin vivo disintegrating may be varied between the disclosed batches. Thedisintegration time should be complete within 60 seconds from the onsetof disintegration or preferable faster.

Since dissolution of nicotine bitartrate is a relatively fast process,the time used to release the content of nicotine can be taken as thedisintegration time of the matrix (here the tablet).

Example 5

Nicotine Release and Absorption

Measurements of nicotine concentration is performed as follows:

One dose of the tablets of example 1 and 2 is administered sublinguallyto at least six individuals. At specified time intervals, the saliva iscollected. The experiment is repeated. Thus, each nicotine concentrationvalue is the arithmetic mean of 12 measurements, i.e. performed onsaliva-samples from six individuals times 2. The nicotine concentrationof saliva is analyzed on HPLC after extraction into relevant buffer.

Results are shown in tables 8A-8C.

TABLE 8A Amount of nicotine in saliva. Measuring time from initialcontact with oral saliva [seconds] 10 20 90 Concentration of nicotine[mg/mL] 2 mg Nicotinell Mint Lozenge 0.06 0.05 0.10 1 mg FDT (12) 0.520.59 0.52 1 mg FDT (13) 0.74 0.66 0.66 1 mg FDT (14) 0.36 0.39 0.33Nicorette Microtab 2 mg 0.03 0.05 0.13 Nicotinell Mint Chewing gum 0.020.04 0.18 (2 mg) N/A = Not applicable (not assessed)

TABLE 8B Amount of nicotine in residue. Measuring time from initialcontact with oral saliva [seconds] 10 20 90 Concentration of nicotine[mg/mL] 2 mg Nicotinell Mint Lozenge 1.90 1.91 1.85 1 mg FDT (12) Noresidue No residue No residue 1 mg FDT (13) No residue No residue Noresidue 1 mg FDT (14) N/A N/A No residue Nicorette Microtab 2 mg 1.901.87 1.77 Nicotinell Mint Chewing gum 1.98 1.96 1.72 (2 mg) N/A = Notapplicable (not assessed)

TABLE 8C Absorption of nicotine. Measuring time from initial contactwith oral saliva [seconds] 10 20 90 Absorption of nicotine [% by weight]2 mg Nicotinell Mint Lozenge 2 2 3 1 mg FDT (12) 48 41 48 1 mg FDT (13)26 34 35 1 mg FDT (14) N/A N/A 67 Nicorette Microtab 2 mg 4 4 5Nicotinell Mint Chewing gum 0 0 5 (2 mg) N/A = Not applicable (notassessed)

As can be seen from table 8A-8C, formulations of the invention providedvery high absorption, above 40% or even above 50%. Also, since FDT 12and 13 are comparable, only that FDT 13 does not contain buffer, theeffect of inclusion of the buffer may be observed. It is noted thatFDT12 has a final absorption being significantly higher than FDT13,illustrating how inclusion of buffer increases the absorption ofnicotine. Also, it is observed that the absorption of nicotine is moreor less constant at times 10 seconds, 20 seconds, and 90 seconds,illustrating how the disintegration time (about seconds for FDT 12) isthe limiting factor, and that the time for release of nicotine afterdisintegration as well as the time for absorption of nicotine isnegligible for the present compositions.

The tablets of the example 1 and 2 are highly suitable to obtain orallydisintegrating nicotine tablets for nicotine craving relief comprising apressed powder formulation, the tablet being designed to disintegratewithin a period of less than 60 seconds upon oral administration, thepowder formulation comprising an amount of nicotine and a pH regulatingagent.

Example 6

Evaluation of Fast Disintegrating Tablets—Burning

In general experiments have disclosed that nicotine fast disintegratingtablets according to the invention result in high absorption efficiencyof nicotine into the blood stream for a fast disintegrating tablet user.With such fast integration, high pH-value combined with high nicotineconcentration, only a minor part of the nicotine is swallowed by theuser instead of entering the blood system, thereby resulting in fastcraving relief.

When pH in the mouth is high, the nicotine is used in a very efficientway. However, too high pH in the saliva of the fast disintegratingtablet users may not be desirable, since the highly alkaline pH-valueresults in problems with irritation and burning of the sublingualtissue.

Consequently, the fast disintegrating tablets of the invention areindeed suitable in that they provide an efficient utilization ofnicotine and at the same time are pleasant to the user, i.e. withclearly diminished unwanted side effects, hereunder particularly socalled nicotine burning in the throat.

Evaluation of burning sensation is performed as described in thefollowing.

Nicotine burning was evaluated by a test panel of 7 trained assessors.After calibration by means of chewing two standard nicotine containingchewing gum with “known” burning intensity, each assessor evaluates theburning sensation in the throat on a scale from 1 to 15, where 15 is themost intense burning. Each assessor evaluates all samples twice. Theevaluations are noted for the time periods indicated. Average values arecalculated.

TABLE 9 Sensory evaluation of throat burning. Time [seconds] 145 295 505Burning score (1-15) FDT (12) 3.5 1.8 0.8 FDT (14) 6.6 4.5 2.7Nicotinell Mint Chewing gum (2 mg) 4.6 4.6 3.4 Nicotinell Mint Lozenge(2 mg) 4.8 4.9 4.2 Nicorette Microtab (2 mg) 6.4 5.9 5.5

Example 7

Alleviation of Nicotine Craving

Nicotine craving alleviation was tested using a panel of three usersevaluating all samples twice. Each user noted the time from oraladministration until craving relief, i.e. feeling the effect of nicotinereaching the head. The average times for FDT (12) and FDT (14) and threecommercially available products are indicated in table 10.

TABLE 10 Time before alleviation. Nicotinell Mint Nicotinell MintNicorette Time before FDT FDT Chewing gum Lozenge Microtab alleviation(12) (14) (2 mg) (2 mg) (2mg) Average 240 300 560 480 400

As can be seen from table 10, significantly faster alleviation wasobtained compared to the commercially available products.

The invention claimed is:
 1. A fast orally disintegrating nicotinetablet for nicotine craving relief comprising a pressed powderformulation, wherein the tablet disintegrates within a period of lessthan 60 seconds upon oral administration, wherein the pressed powderformulation comprises an amount of nicotine, a pH regulating agent, atleast one polyol, and a disintegrant, wherein the tablet comprises thepolyol in an amount of more than 40% by weight of the tablet, whereinthe tablet comprises the disintegrant in an amount of 1-10% by weight ofthe tablet, wherein the pH regulating agent provides a pH of more than 8during the disintegration of the tablet, and wherein the tabletsubstantially reduces the side effect of burning.
 2. The tabletaccording to claim 1, wherein the tablet disintegrates within a periodof less than 30 seconds upon oral administration.
 3. The tabletaccording to claim 1, wherein the amount of nicotine dissolves within aperiod of less than 90 seconds upon oral administration.
 4. The tabletaccording to claim 1, wherein the tablet comprises nicotine in theamount of at least 0.5 mg.
 5. The tablet according to claim 1, whereinsaid nicotine is provided as a nicotine salt.
 6. The tablet according toclaim 5, wherein the nicotine salt is nicotine bitartrate.
 7. The tabletaccording to claim 1, wherein said nicotine is provided as a complexbetween nicotine and an ion exchange resin.
 8. The tablet according toclaim 1, wherein said nicotine is provided in association with a fattyacid.
 9. The tablet according to claim 1, wherein said nicotine isprovided as an ionic complex with at least one mucoadhesivewater-soluble anionic polymer.
 10. The tablet according to claim 1,wherein said nicotine is provided as a synthetic nicotine.
 11. Thetablet according to claim 1, wherein the tablet is a sublingual tablet.12. The tablet according to claim 1, wherein the pressed powderformulation comprises at least one polyol and wherein the polyolcomprises more than 59% by weight of the tablet.
 13. The tabletaccording to claim 1, wherein the tablet is pressed at a pressure of2-20 kN.
 14. The tablet according to claim 1, wherein the formulationprovides a peak saliva concentration of nicotine of more than 0.3 mg/mLand a peak saliva pH of more than 8 during the first 120 seconds uponoral administration.
 15. The tablet according to claim 1, wherein theamount of nicotine dissolves within a period of less than 90 secondsupon oral administration, and wherein at least 40% by weight of thenicotine is absorbed through the oral mucosa.
 16. The tablet accordingto claim 1, wherein the disintegrant comprises cross-linkedpolyvinylpyrrolidone.
 17. The tablet according to claim 1, wherein thetablet comprises the disintegrant in an amount of 2-8% by weight of thetablet.
 18. The tablet according to claim 1, wherein the tablet has aweight of 50 to 150 mg.
 19. A method of alleviation of nicotine cravingby administering said orally disintegrating nicotine tablet according toclaim
 1. 20. The tablet according to claim 1, wherein the pressed powdercomprises at least one polyol and wherein the polyol comprises more than69% by weight of the tablet.
 21. The tablet according to claim 1,wherein the at least one polyol is selected from the group consisting ofsorbitol, erythritol, xylitol, maltitol, mannitol, lactitol, andisomalt.
 22. The tablet according to claim 1, wherein the at least onepolyol is mannitol.
 23. A fast orally disintegrating nicotine tablet fornicotine craving relief comprising a pressed powder formulation, whereinthe tablet disintegrates within a period of less than 60 seconds uponoral administration, wherein the pressed powder formulation comprises anamount of nicotine, a pH regulating agent, at least one polyol, and adisintegrant, wherein the tablet comprises the polyol in an amount ofmore than 40% by weight of the tablet, wherein the tablet comprises thedisintegrant in an amount of 1-10% by weight of the tablet, wherein thepH regulating agent provides peak saliva pH of more than 8 during thefirst 120 seconds upon oral administration, and wherein the tabletsubstantially reduces the side effect of burning.
 24. A fast orallydisintegrating nicotine tablet for nicotine craving relief comprising apressed powder formulation, wherein the tablet disintegrates within aperiod of less than 60 seconds upon oral administration, wherein thepressed powder formulation comprises an amount of nicotine, a pHregulating agent, at least one polyol, and a disintegrant, wherein thetablet comprises the polyol in an amount of more than 40% by weight ofthe tablet, wherein the tablet comprises the disintegrant in an amountof 1-10% by weight of the tablet, wherein the orally disintegratingtablet does not comprise an outer coating, wherein the pH regulatingagent provides a pH of more than 8 during the disintegration of thetablet, and wherein the tablet substantially reduces the side effect ofburning.
 25. The tablet according to claim 1, wherein the tablet has aweight of 25 to 200 mg.